Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma

Combining antibody-drug conjugates (ADCs) with targeted small-molecule inhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30+/ALK+ anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib. Furthermore, treatment with anti-CD30-LDM plus crizotinib resulted in a stronger induction of cell apoptosis than monotherapy with either treatment. Western blot analysis revealed that ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Interestingly, the addition of crizotinib inhibited the expression of phosphorylated ERK1/2 and further augmented anti-CD30-LDM-mediated apoptosis, providing a potential synergistic mechanism for DNA-damagi..... READ ARTICLE

Cancer Letters
DOI:10.1016/j.canlet.2019.02.002

Authors: Rong Wang, Liang Li, Aijun Duan, Yi Li, Xiujun Liu, Qingfang Miao, Jianhua Gong, Yongsu Zhen